title: NO-donating genistein prodrug alleviates bone loss in ovariectomised rats.
abstract: OBJECTIVE
  To find a more potent alternative with less oestrogen-related side effects for hormone replacement therapy (HRT) in postmenopausal osteoporosis, we designed and synthesized a NO-releasing prodrug of genistein (NO-G) according to the structure of NONSAIDs. The purpose of this study was to evaluate the effects of the prodrug on bone in ovariectomised (OVX) rats.
  
  
  METHODS
  Forty-eight adult Sprague-Dawley female rats were ovariectomised and treated with vehicle, 9 mg/kg genistein and 4.5, 9 or 18 mg/kg NO-G by oral administration daily. The bioassays were performed in terms of bone mineral density (BMD), mechanical testing, bone formation markers, bone alkaline phosphatase (b-ALP) and osteocalcin (OCN) and bone resorption marker urine deoxypyridinoline (DPD). In addition, the effects of the drugs on uterus and body weight were examined.
  
  
  RESULTS
  After treatment for 12 weeks, the BMD of whole femur and tibia in the NO-G (9 and 18 mg/kg) groups were 12.1% and 12.2% higher than that of OVX group (P<0.01); the bending strength of the femur was 11.2% and 12.2% higher than OVX group (P<0.01). The OVX-induced increase of serum b-ALP, OCN and urinary DPD were markedly attenuated. The prodrug showed no side effects on uterus and body weight.
  
  
  CONCLUSIONS
  The NO-releasing prodrug of genistein improves the bone loss in OVX rats without stimulatory effects on the uterus, which suggests that the product could potentially be used for the prevention and treatment of postmenopausal osteoporosis.
authors.affiliation: Institute of Materia Medica, School of Pharmacy, Fourth Millitary Medical University, Xi'an, Shaanxi, People's Republic of China.
authors.forename: Jiepin
authors.initials: J
authors.lastname: Wang
authors.forename: Fujun
authors.initials: F
authors.lastname: Shang
authors.forename: Qibing
authors.initials: Q
authors.lastname: Mei
authors.forename: Jianbo
authors.initials: J
authors.lastname: Wang
authors.forename: Rong
authors.initials: R
authors.lastname: Zhang
authors.forename: Siwang
authors.initials: S
authors.lastname: Wang
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001835:Body Weight; D015519:Bone Density / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D019833:Genistein / Q000008:administration & dosage / Q000627:therapeutic use*; D009569:Nitric Oxide / Q000378:metabolism*; D010024:Osteoporosis / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D010052:Ovariectomy / Q000009:adverse effects; D048789:Phytoestrogens / Q000008:administration & dosage / Q000627:therapeutic use*; D011355:Prodrugs; D051381:Rats; D017207:Rats, Sprague-Dawley; D016896:Treatment Outcome
chemical_list: D048789:Phytoestrogens; D011355:Prodrugs; D009569:Nitric Oxide; D019833:Genistein